Genetic counseling: CADASIL
CADASIL CADASIL = Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and *Leukoencephalopathy (destruction of myelin sheath covering nerves) *Microangiopathy (disease of the arteries) mainly affecting the brain Contracting *Welcome and Introductions. *I understand you have come to discuss your family history of CADASIL disease. *Why have you sought out genetic counseling at this point in your life? *What do you already know about CADASIL? How familiar are you with your family history? What reading/research have you done on your own? Why are you interested in genetic testing? *What are you hoping the test can tell you? What are you planning to do with the information? How will the results affect your life? *Set agenda: get a little more information about your family, review CADASIL, talk about the different kinds of testing available (what they can tell us, how sensitive they are, how much they cost), and help you make a decision about testing Intake *Review medical history **Any health concerns? Any problems with migraines, depression, TIA's, high blood pressure, memory loss? **Has you doctor been screening you for any signs or symptoms? **Have you ever had a brain MRI? Skin biopsy? *Review family history Disease Characteristics *Symptoms (variable phenotype) **migraine headaches (w/ or w/out aura-- sensations of lights, voices or numbness) (40 to 60%) **recurring TIA's and strokes (>80%) **cognitive and behavioral disturbances (extent is variable) **psychiatric disturbances (depression, personality changes) (~30%) **dementia (subcortical type - memory disturbances, psychic slowing, loss of initiative) (>85% in patients older than 65) **pseudo-bulbar palsy -- slurred speech, difficulty with swallowing, weakness of face, tongue, and swallowing muscles, a tendency for uncontrollable laughter or crying, and brisk jaw and gag reflexes due to the degeneration or loss of the lower motor neurons (in the brainstem) that supply nerves to the muscles of the throat, larynx, face etc **epilepsy (10%) **diffuse white matter lesions and subcortical infarcts on neuroimaging *Ages of Onset **Variable (even within the same family) **Mid-Adult onset (30's - 60's) **extensive testing has identified individuals who have relatively mild disease, or may even be clinically unaffected in the 7th or 8th decade *Progression/Stages of disease **migraines first occur at a mean age of 26 **TIA's and stroke beginning, on average, at 45 years of age (range 20-60's) **Cognitive decline can start as early as 35 years of age (by age 45, more than 50% of patients have it) **Dementia/severe cognitive deficits by age 65 **Death usually in the 7th decade Genetic Etiology *Due to mutations in the NOTCH3 gene (19p13.2-13.1) **identified in >90% of patients **all pathogenic sequence alterations result in the gain or loss of a single cysteine residue (95% of mutations are missense) **penetrance is probably 100% *Autosomal dominant inheritance **affected person has a 50/50 chance of passing it on to each child ***If your mom is not affected, then you are not going to be. If you are not affected, then your daughter is not going to be. **de novo mutations are rare *Prevalence is unknown **some 200 families have been described from all continents, but most have been of European origin **many families are likely undiagnosed or misdiagnosed Testing *Diagnostic Testing **Neuroimaging (MRI) ***diffuse periventricular and deep white matter lesions ***subcortical infarcts in white matter, basal ganglia, and brain stem ***external capsules and temporal lobes are often affected ****Leukoencephalopathy is often present on MRI before developing symptoms ****When white matter abnormalities are absent on MRI of a person older than 35 years of age, CADASIL is usually excluded. ****Sensitivity 89-93%, specificity 45-86% **Skin biopsy (Electron Microscope evaluation) ***electron dense granules in the media of arterioles ***granular osmiophilic material in the media ****Sensitivity 45%, specificity 100% (false negative rate is unknown) ****New immunostaining technique has a sensitivity of 96% and specificity of 100% *Genetic Testing **Available on clinical basis at Athena and CHOP **Identifies 90-95% of mutations ****Scanning of the 5 exons with the highest mutation frequencies (3, 4, 11, 18, 19) detects 87% of patients with skin biopsy-confirmed CADASIL ****When testing at-risk people, an affected family member should be tested first to confirm that the mutation is identifiable by currently available techniques. ****To get the most information, we need to know an identified mutation in an affected relative ****Otherwise, we will not be able to rule CADASIL out completely (even with a negative genetic test because we won't know if you have a mutation that they just couldn't find) **Possibility of a variant of uncertainty **Prenatal testing is available for identified mutations (uncommon request since adult-onset disorder) Psychosocial Counseling *Motivations for testing (reproduction, career, financial matters, need to know) **Testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression *How will you feel if you pay the money to have the testing, but we don't really know the answer for sure? *Future life plans *Concern about insurance/employment discrimination *There is no preventative or symptomatic therapies available **many neurologists prescribe salicylates - no studies on whether these have any effect on preventing stroke **angiography and anti-coagulants are contraindicated because they may provoke cerebrovascular accidents What if this turns out to not be CADASIL? What if it is something else we cannot test for? *Make decision and establish plan for testing and follow-up Resources *GeneClinics handout *United Leukodystrophy Foundation, Inc. :2304 Highland Drive :Sycamore, IL 60178 :1-800-728-5483 or 815-895-3211 :http://www.ulf.org *(personal family webpage) *(online support group) *-- research project on cadasil at UCLA References *"CADASIL." GeneReviews. www.geneclinics.org *Markus HS et al. "Diagnostic Strategies in CADASIL." Neurology 2002; 59: 1134-1138. *Joutel A et al. "Skin Biopsy Immunostaining with a Notch3 Monoclonal Antibody for CADASIL Diagnosis." Lancet 2001; 358: 2049-2051. *Mayer M et al. "Muscle and Skin Biopsies are a Sensitive Diagnostic Tool in the Diagnosis of CADASIL." J Neurology 1999; 246: 526-532. MRI *Approximately 90% of individuals with CADASIL will show white matter abnormalities *CADASIL can usually be ruled out in individuals over age 35 if no abnormalities are found on MRI Skin Biopsy (electron microscope evaluation) *Detection of a substance called granular osmiophilic material in the small blood vessels is diagnostic *Substance only detected in about half of individuals with CADASIL *Immunostaining is being developed which detects approximately 96% of individuals with CADASIL Genetic Testing *Mutation scanning and sequencing available for up to 23 of the 33 exons in NOTCH3 *If a disease associated mutation is found in an asymptomatic individual than the individual will likely develop symptoms eventually *If a disease associated mutation is not found in an asymptomatic individual than we don't know if it is because they didn't inherit the mutation present in the family or if a mutation was not found due to limitations of the test *Therefore it is best to test a family member with CADASIL first *Chance that a variant of uncertain significance could be identified Notes The information in this outline was last updated in 2002. Material obtained under GFDL Licence from http://en.wikibooks.org/wiki/Handbook_of_Genetic_Counseling